1. Field of the Invention
The present invention relates to a delivery composition for oral delivery of materials with poor water solubility. In particular, the invention is directed to particulate compositions consisting of individual, non-agglomerated composite particles using fine carrier particles to deliver nano-sized drug or active materials in oral dosage forms, and to processes for producing them.
1. Description of the Related Technology
Active pharmaceutical ingredients with poor solubility in water have low bioavailability, which leads to only a small portion of the pharmaceuticals being available to the target tissue after administration to a patient. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions. Poorly water soluble pharmaceuticals, i.e., those having a water solubility of less than about 10 mg/ml, tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.
It is known that the rate of dissolution of a particulate pharmaceutical ingredient can increase with increasing surface area, i.e., decreasing particle size. Consequently, methods of making finely divided pharmaceutical compositions have been studied and efforts have been made to control the size and size range of particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and hence influence drug absorption. Wet grinding may also be beneficial in further reducing particle size, but aggregation/agglomeration or flocculation often restricts the lower particle size limit to approximately 10 microns (10,000 nm).
Other techniques for preparing pharmaceutical compositions include loading drugs into liposomes or polymers, e.g., during emulsion polymerization. However, such techniques have problems and limitations. For example, a lipid soluble drug is often required in preparing suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses. Further still, techniques for preparing such pharmaceutical compositions tend to be complex. A principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator, which can be toxic, at the end of the manufacturing process.
There is also a need for preparing dry dosage forms containing nanodrug particles. Simple spray drying, freeze drying or lyophilization may lead to poor flowing, low bulk density products. An alternate approach is to form core-shell composite particles; preferably with finer carrier particles. However, finer particles do not flow well, and they certainly do not fluidize well. Therefore, methods for improving their flow and fluidizability are desired. Yang et al. discloses several dry processing techniques for coating cohesive cornstarch powder with different size silica particles (Yang, J., Sliva, A., Banerjee, A., Dave, R. N., and Pfeffer, R., “Dry particle coating for improving the flowability of cohesive powders,” Powder Technology, vol. 158 (2005) 21-22). The flowability of the coated cornstarch can in some cases be influenced by using nanosized silica coating.
Chen et al., “Fluidization of Coated Group C Powders,” AIChE Journal, vol. 54 (2008) 104-121 discloses a process of dry coating cohesive, Geldart Group C powders with a very small amount of nano-sized particles. The dry coating is said to improve the fluidizability of the powders.
Chen et al., “Fluidized bed film coating of cohesive Geldart group C powders,” Powder Technology, vol. 189 (2009) 466-480 discloses a process of dry coating cohesive Geldart group C powders process to reduce the interparticle force and improve the fluidization behavior of fine powders. Polymer film coating at an individual particle level is achieved on these pre-coated fine powders in a commercially available spouting fluidized bed (MiniGlatt).
U.S. Pat. No. 7,276,249 discloses a process of spray coating nanosuspensions onto large carrier particles. The coated fibrate compositions are said to have improved pharmacokinetic profiles and reduced fed/fasted variability. The fibrate particles of the composition have an effective average particle size close to about 2000 nm However, these large carrier particles have a relatively low surface area per unit weight of the product which does not allow for sufficient drug loading, which may necessitate a thicker coating layer, which can decrease the dissolution rate of the active ingredients.
A significant issue for prior art processes is irreversible agglomeration of the coated pharmaceutical particles often caused by poor drying methods, which typically leads to particle sizes much larger than 100 μm. The present invention provides a process to produce active pharmaceutical ingredient (API) composite powders that minimizes irreversible agglomeration and particle growth and achieves suitably redispersible nanoparticles which enhance the dissolution of poorly water soluble API's.